Tesofensine and metoprolol for treatment of hypertension

ABSTRACT

The present invention relates to treatment of hypertension using a combination of tesofensine and metoprolol. The treatment is particularly well suited for the treatment of hypertensive obese subjects and hypertensive diabetic subjects.

FIELD OF INVENTION

The present invention relates to the treatment of hypertension using acombination of tesofensine and metoprolol, particularly to the treatmentof hypertensive obese subjects and hypertensive diabetic subjects.

BACKGROUND OF INVENTION

Hypertension, i.e. high blood pressure, is a chronic medical conditionin which the blood pressure in the arteries is persistently elevated.Sustained hypertension over time is a major risk factor for hypertensiveheart disease, coronary artery disease, stroke, aortic aneurysm,peripheral artery disease, and chronic kidney disease. Worldwide, highblood pressure is estimated to cause 7.5 million deaths, about 12.8% ofthe total of all deaths.

Within the past decades the prevalence of obesity has also risen invirtually all ethnic, racial and socioeconomic populations, in bothgenders and in all age groups. Obesity is associated with asignificantly elevated risk for type 2 diabetes, coronary heartdiseases, hypertension and numerous other major illnesses and overallmortality from all causes. Therefore, weight reduction and reduction ofblood pressure is usually critical for the obese patient.

Control of hypertension is also a major focus area in the treatment ofdiabetic subjects since most people with diabetes develop high bloodpressure during their life. Hypertension can lead to and make worse manycomplications of diabetes, including diabetic eye disease and kidneydisease.

Tesofensine, first described in WO 97/30997, is a triple monoaminereuptake inhibitor in clinical development for the treatment of obesity.Tesofensine effectively produces weight loss in obese individuals ofabout twice of that seen with currently marketed anti-obesity drugs. Ingeneral, tesofensine is well tolerated in humans, but at therapeuticrelevant doses it has been found that heart rate and, at higher doses,also blood pressure increased due to a well understood mechanism ofaction driven effect (activation of adrenergic receptors) (Astrup et al2008, Lancet 372:1906-13). Animal studies have shown thatco-administration of tesofensine and metoprolol is capable of preventingthe tesofensine-induced increase in heart rate and blood pressurewithout reducing the weight loss efficacy of tesofensine (WO 2013/120935and Hjorth Bentzen et al 2013; Obesity; Vol 21(5), p. 985-992).

Metoprolol is a selective β1 (adrenergic) receptor blocker. Metoprololhas been used to treat various cardiovascular disorders includingangina, arrhythmias, tachycardia, myocardial infarction, heart failureand hypertension.

The effect of metoprolol on blood pressure has previously beeninvestigated (Kostis et al (Circulation 75(1), 204-212, 1987). Kostis etal has shown that metoprolol treatment decreases supine systolic anddiastolic blood pressure by about 4 mmHg in healthy male subjects.

There is impetus for creating new and alternative treatments formanagement of hypertension and, in particular, management ofhypertension in obese individuals.

SUMMARY OF INVENTION

The present inventors have surprisingly found that co-administration oftesofensine and metoprolol to human subjects results in a significantdecrease in both systolic and diastolic blood pressure. The observedeffect on blood pressure is higher than the effect achievable frommetoprolol alone. The expectation is that Tesofensine increases bloodpressure and that metoprolol may act to prevent this increase in bloodpressure. Therefore it is unexpected that the combination leads to adecrease in blood pressure. The blood pressure lowering effect ofco-administration of Tesofensine with Metoprolol has been confirmed inhealthy subjects (example 2) and in subjects with Type 2 diabetes(example 3). The experimental data also confirm that the combination ofTesofensine with Metoprolol is effective in inducing weight loss and inreducing blood pressure at the same time.

Thus, the present invention relates to the use of tesofensine andmetoprolol for reduction of blood pressure, i.e. in one aspect fortreatment of hypertension.

In a first aspect, the present disclosure relates to a method fortreatment of hypertension in a subject, the method comprisingadministering to said subject in need thereof:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure in said subject.

In another aspect, the present disclosure relates to a method forreducing blood pressure in a subject, the method comprisingadministering to said subject in need thereof:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure in said subject.

The present disclosure further relates to a composition comprising

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        for use in the treatment of hypertension or for reduction of        blood pressure.

In yet another aspect, the present disclosure relates to use of thecomposition as described herein in the manufacture of a medicament forthe treatment of hypertension or for reduction of blood pressure.

Co-treatment with tesofensine and metoprolol is capable of reducing bothweight and blood pressure in a subject. Thus, in yet another aspect, thepresent disclosure relates to a method for treatment of hypertension andobesity in a subject in need thereof, the method comprisingadministering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and

ii) a therapeutically effective amount of metoprolol or apharmaceutically acceptable salt thereof,

thereby reducing blood pressure and body weight of said subject.

The composition comprising tesofensine and metoprolol as describedherein is particularly well suited for use in the treatment ofhypertensive obese and/or diabetic subjects.

DESCRIPTION OF DRAWINGS

FIG. 1. PK of metoprolol after a single dosing in absence and presenceof tesofensine at steady state. Single dose metoprolol pharmacokinetics(PK, 50 mg/kg) obtained at day 0 was compared to the PK obtained after14 days of tesofensine once daily administration (2 mg loading dose atdays 1-3, 0.5 mg maintenance dose at days 4-14).

FIG. 2. Increase in heart rate (HR) caused by 14 days tesofensine dosingis suppressed by a single metoprolol administration. Column 1: prelevelHR; column 2: HR after 14 days of tesofensine; column 3: HR measured onday 14, 7 hours after a single metoprolol dose in tesofensine treatedsubjects; column 4: HR measured on day 15, 24 hours after a singlemetoprolol dose in tesofensine treated subjects. *p<0.05 vs tesofensine,## p<0.01 vs prelevel. By ‘t’ test Wilcoxon matched-pairs signed ranktest.

FIG. 3. Systolic and diastolic blood pressure after 14 days tesofensinedosing followed by a single metoprolol administration. A singlemetoprolol administration reduced both systolic and diastolic bloodpressure (BP) in tesofensine treated subjects to levels belowpretreatment levels. Column 1: prelevel BP; column 2: BP after 14 daysof tesofensine; column 3: BP measured on day 14, 7 hours after a singlemetoprolol dose in tesofensine treated subjects; column 4: BP measuredon day 15, 24 hours after a single metoprolol dose in tesofensinetreated subjects. ** P<0.01 vs tesofensine (Wilcoxin matched-pairssigned rank test, n=14).

DETAILED DESCRIPTION OF THE INVENTION

The data in the present application shows that tesofensine andmetoprolol co-administration efficiently reduces blood pressure,wherefore their combined use is proposed herein for the treatment ofhypertension. The data also confirm that tesofensine and metoprololco-administration effectively reduces weight and blood pressure,wherefore the combined use is proposed herein for the treatment ofhypertension and obesity or an obesity related disorder as hereindefined.

Tesofensine

The treatment described herein comprises administration of an activepharmaceutical ingredient (API) selected from tesofensine or apharmaceutically acceptable salt thereof.

Tesofensine[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane]is a centrally acting triple monoamine re-uptake inhibitor (MRI) withintrinsic inhibitory activity on noradrenaline, serotonin and dopaminetransporter function. When corrected for placebo and diet effects,long-term tesofensine treatment produces a weight loss of about 10% inobese patients, which is approximately twice as much as that achieved bycurrently marketed anti-obesity drugs.

The chemical structure of tesofensine is

Preclinical and clinical data suggest that appetite suppression is animportant mechanism by which tesofensine exerts its robustweight-reducing effect. In addition, tesofensine has also beendemonstrated to increase nocturnal energy expenditure in human subjects.These findings have recently been corroborated and extended inpreclinical settings, demonstrating that tesofensine induces a robustand sustained weight loss in a rat model of diet-induced obesity (DIO)of which the long-lasting reduction in body weight is caused by appetitesuppression with a gradual increase in energy expenditure. Notably, thehypophagic effect of tesofensine in DIO rats is critically dependent onstimulated al adrenoceptor activity, and to a less extend dopamine D1receptor function, indicating that enhancement of central noradrenergicand dopaminergic neurotransmission constitute important mechanismsunderlying the robust appetite-suppressing effect of tesofensine.

Overall, chronic tesofensine treatment is associated with minor adverseevents, and with minimal cardiovascular effects, suggesting thattesofensine may generally be a well-tolerated long-term treatment forobesity. However, dose-dependent elevations in heart rate andsignificant increases in blood pressure have been reported in obeseindividuals.

Examples of pharmaceutically acceptable salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzene-sulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Examples of pharmaceutically acceptable cationic salts of an APIinclude, without limitation, the sodium, the potassium, the calcium, themagnesium, the zinc, the aluminium, the lithium, the choline, thelysinium, and the ammonium salt, and the like, of an API containing ananionic group. Such cationic salts may be formed by procedures wellknown and described in the art.

In the context of this disclosure the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

In one embodiment of the present disclosure, tesofensine is selectedfrom the free base, the citrate salt and the tartrate salt.

The tesofensine or pharmaceutically acceptable salt thereof is usuallyadministered orally.

Tesofensine is normally administered at a daily dose of about 0.25-2 mgAPI (active pharmaceutical ingredient).

In one embodiment of the present disclosure tesofensine orpharmaceutical salt thereof is administered at about 0.25 mg or about0.5 mg API per day, such as at about 0.2 mg to about 0.3 mg or about0.45 to about 0.55 mg API per day.

In one embodiment of the present disclosure tesofensine orpharmaceutical salt thereof is administered in a range of from about 0.1mg to about 4 mg API per day, such as about 0.1 mg to about 3 mg API perday, for example about 0.1 to about 2.5 mg API per day, such as about0.1 to about 2 mg API per day, such as about 0.1 to about 1.5 mg API perday, for example about 0.1 mg to about 1 mg API per day, such as about0.1 mg to about 0.8 mg API per day, for example about 0.1 mg to about0.7 mg API per day, such as about 0.1 mg to about 0.6 mg API per day,for example about 0.1 mg to about 0.5 mg API per day, such as about 0.1mg to about 0.4 mg API per day, for example about 0.1 mg to about 0.3 mgAPI per day, such as about 0.1 mg to about 0.2 or about 0.2 to about 0.3mg API per day.

In one embodiment of the present disclosure tesofensine is administeredin a range of from about 0.5 mg to about 4 mg API per day, such as about1 mg to about 4 mg API per day, for example about 1.5 mg to about 4 mgAPI per day, such as about 2 mg to about 4 mg API per day.

In one embodiment, the tesofensine or a pharmaceutically acceptable saltthereof is administered at 0.1-1.5 mg API per day, for example 0.1-1 mgAPI per day, such as 0.2-0.8 mg API per day, for example 0.25-0.75 mgAPI per day, such as 0.4-0.6 mg API per day, for example about 0.2 mgAPI per day, 0.25 mg API per day, 0.5 mg API per day or 0.75 mg API perday.

In one embodiment of the present disclosure tesofensine is administeredin a range of from about 0.01 mg to about 0.4 mg API per day, such asabout 0.01 mg to about 0.3 mg API per day, for example about 0.01 mg toabout 0.2 mg API per day, such as about 0.01 mg to about 0.1 mg API perday.

In one embodiment of the present disclosure tesofensine is administeredin a range of from about 0.05 mg to about 0.4 mg API per day, such asabout 0.05 mg to about 0.3 mg API per day, for example about 0.05 mg toabout 0.2 mg API per day, such as about 0.05 mg to about 0.1 mg API perday.

In one embodiment of the present disclosure tesofensine is administeredin a range of from about 0.05 mg to about 0.10 mg API per day, such asabout 0.10 mg to about 0.15 mg API per day, for example about 0.15 mg toabout 0.20 mg API per day, such as about 0.20 mg to about 0.25 mg APIper day.

In one embodiment, the tesofensine or a pharmaceutically acceptable saltthereof is administered at about 0.1-0.3 mg API per day.

In one embodiment, the tesofensine or a pharmaceutically acceptable saltthereof is administered at about 0.2-0.4 mg API per day.

In one embodiment, the tesofensine or a pharmaceutically acceptable saltthereof is administered at about 0.4-0.6 mg API per day.

In one embodiment, the tesofensine or a pharmaceutically acceptable saltthereof is administered at about 0.6-0.8 mg API per day.

The daily dosage of tesofensine may be administered in one or severaldoses, such as two, per day. In one embodiment, the daily dosage isadministered in one dose.

Metoprolol

Metoprolol, i.e.1-(Isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol, brandedunder various trade names, is a selective β1 (adrenergic) receptorblocker. Metoprolol has been used to treat various cardiovasculardisorders including angina, arrhythmias, tachycardia, myocardialinfarction, heart failure and hypertension. The plasma T_(1/2) formetoprolol is 3-4 hours.

Common side effects of metoprolol include trouble sleeping, feelingtired, feeling faint, and abdominal discomfort. Large doses may causeserious toxicity. Metoprolol has also been reported to lead to weightgain (Messerli et al, The American Journal of Medicine (2007) 120,610-615).

Suitable pharmaceutically acceptable salts of metoprolol include any ofthe salts mentioned herein and preferably include the tartrate,succinate, fumarate or benzoate salts and especially the succinate salt.The S-enantiomer of metoprolol or a salt thereof, particularly thebenzoate salt or the sorbate salt, may also be used.

In one embodiment of the present disclosure metoprolol or apharmaceutically acceptable salt thereof is administered at 10-200 mgAPI per day, such as 25-100 mg API per day or 50-150 mg API per day, forexample 80-120 mg API per day, such as 90-110 mg API per day.

In one embodiment of the present disclosure metoprolol or apharmaceutically acceptable salt thereof is administered at 10-100 mgAPI per day, such as 10-80 mg API per day, for example 10-50 mg API perday, such as 10-30 mg API per day.

The metoprolol or pharmaceutically acceptable salt thereof is usuallyadministered orally.

The daily dosage of metoprolol may be administered in one or severaldoses per day. In one embodiment, the daily dosage is administered intwo or more doses.

In one embodiment, the metoprolol is administered as a pharmaceuticalcomposition having an extended release profile, e.g. as disclosed in WO2016/138908 (incorporated by reference).

Co-Administration of Tesofensine and Metoprolol

According to the present disclosure tesofensine is co-administered withmetoprolol for the treatment or alleviation of hypertension in a subjectin need thereof. Preferably, the treatment disclosed herein results in areduction of blood pressure exceeding that of metoprolol treatmentalone.

Thus, in one embodiment, the present disclosure relates to a method fortreatment of hypertension in a subject, the method comprisingadministering to said subject in need thereof:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure in said subject.

Hypertension usually does not cause symptoms initially, but sustainedhypertension over time is a major risk factor for hypertensive heartdisease, coronary artery disease, stroke, aortic aneurysm, peripheralartery disease, and chronic kidney disease.

Blood pressure is expressed by two measurements, the systolic anddiastolic pressures, which are the maximum and minimum pressures,respectively, in the arterial system. The systolic pressure occurs whenthe left ventricle is most contracted; the diastolic pressure occurswhen the left ventricle is most relaxed prior to the next contraction.The blood pressure values given herein represent values at rest, e.g.supine blood pressure, unless otherwise indicated.

In people aged 18 years or older hypertension is defined as a systolicand/or a diastolic blood pressure consistently higher than an acceptednormal value—see table herein below.

Category Systolic, mm Hg Diastolic, mm Hg Normal  90-119 60-79 HighNormal (pre-hypertension) 120-139 80-89 Stage 1 hypertension 140-15990-99 Stage 2 hypertension 160-179 100-109 Stage 3 hypertension ≥180≥110 (hypertensive emergency) Isolated systolic hypertension ≥140   <90

In some instances, lower thresholds for classification of hypertensionmay be used (135 mmHg systolic or 85 mmHg diastolic), e.g. ifmeasurements are derived from 24-hour ambulatory or home monitoring.

Treatment of hypertension is to be understood herein as a reduction inblood pressure considered clinically relevant by the skilled person.Clinical trials demonstrate that lowering blood pressure cansubstantially reduce cardiovascular risk, and current clinical practiceguidelines identify lowering blood pressure as a priority in thetreatment of people with hypertension.

Preferably, the treatment described herein results in a decrease in thesystolic blood pressure and/or a decrease in the diastolic bloodpressure.

In one embodiment, the subject treated according to the methods of thepresent disclosure is a pre-hypertensive subject having a systolic bloodpressure in the range of 120-139 mmHg and a diastolic blood pressure inthe range of 80-89 mmHg.

In one embodiment, the subject has a systolic blood pressure above 135mmHg and/or a diastolic blood pressure above 85 mmHg.

In one embodiment, the subject has a systolic blood pressure above 140mmHg and/or a diastolic blood pressure above 90 mmHg.

In one embodiment, the subject suffers from stage 1 hypertension, i.e.said subject has a systolic blood pressure in the range of 140-159 mmHgand a diastolic blood pressure in the range of 90-99 mmHg.

In one embodiment, the subject suffers from stage 2 hypertension, i.e.said subject has a systolic blood pressure in the range of 160-179 mmHgand a diastolic blood pressure in the range of 100-109 mmHg.

In one embodiment, the subject suffers from stage 3 hypertension, i.e.said subject has a systolic blood pressure at or above 180 mmHg and adiastolic blood pressure at or above 110 mmHg.

In one embodiment, the subject suffers from isolated systolichypertension, i.e. said subject has a systolic blood pressure at orabove 140 mmHg and a diastolic blood pressure below 90 mmHg.

In children and adolescents (<18 years), hypertension is defined aselevated blood pressure over several visits (The Fourth Report on theDiagnosis, Evaluation, and Treatment of High Blood Pressure in Childrenand Adolescents; Pediatrics, August 2004, VOLUME 114/ISSUE Supplement2). The definition of hypertension in children and adolescents is basedon the normative distribution of blood pressure (BP) in healthychildren. Normal BP is defined as systolic blood pressure (SBP) anddiastolic blood pressure (DBP) that are <90th percentile for gender,age, and height. Hypertension is defined as average SBP or DBP that is95th percentile for gender, age, and height on at least 3 separateoccasions. Average SBP or DBP levels that are 90th percentile but <95thpercentile had been designated as “high normal” and were considered tobe an indication of heightened risk for developing hypertension. It isnow recommended that, as with adults, children and adolescents with BPlevels 120/80 mm Hg but <95th percentile should be consideredprehypertensive.

In one embodiment the subject is below 18 years of age. Children withhypertension may suffer from one or more of diabetes, pre-diabetes,obesity, overeating or Prader Willi syndrome.

In one embodiment, the treatment results in a decrease in the systolicblood pressure by at least 5 mm Hg, for example at least 6 mm Hg, suchas at least 7 mm Hg, for example at least 8 mm Hg, such as at least 9 mmHg, for example at least 10 mm Hg, such as at least 12 mm Hg, forexample at least 15 mm Hg, such as at least 17 mm Hg, for example atleast 20 mm Hg, such as at least 22 mm Hg, for example at least 25 mmHg, such as at least 27 mm Hg, for example at least 30 mm Hg.

In one embodiment, the treatment results in a decrease in the systolicblood pressure by at least 10 mm Hg.

In one embodiment the treatment results in a decrease in the systolicblood pressure by at least 5%, such as at least 7%, for example at least10%, such as at least 12%, for example at least 15%, such as at least17%, for example at least 20%, such as at least 22%, for example atleast 25%.

In one embodiment, the treatment results in a decrease in the diastolicblood pressure by at least 5 mm Hg, for example at least 6 mm Hg, suchas at least 7 mm Hg, for example at least 8 mm Hg, such as at least 9 mmHg, for example at least 10 mm Hg, such as at least 12 mm Hg, forexample at least 15 mm Hg, such as at least 17 mm Hg, for example atleast 20 mm Hg, such as at least 22 mm Hg, for example at least 25 mmHg, such as at least 27 mm Hg, for example at least 30 mm Hg.

In one embodiment, the treatment results in a decrease in the diastolicblood pressure by at least 10 mm Hg.

In one embodiment, the treatment results in a decrease in the diastolicblood pressure by at least 5%, such as at least 7%, for example at least10%, such as at least 12%, for example at least 15%, such as at least17%, for example at least 20%, such as at least 22%, for example atleast 25%.

Control of hypertension is a particular focus area in obese subjects,since subjects suffering from obesity often also suffer fromhypertension. The present treatment allows for concurrent treatment ofhypertension and obesity. Obesity is defined herein as a medicalcondition in which excess body fat has accumulated to the extent that itmay have an adverse effect on health, leading to reduced life expectancyand/or increased health problems in general. Thus, in one embodiment thesubject is obese.

Body mass index (BMI) is a measure which compares weight and height.People are generally considered overweight or pre-obese if the BMI isbetween 25 and 30 and obese if the BMI is over 30. Morbidly obesesubjects have a BMI over 35.

In one embodiment the subject has a BMI above 25 kg/m², such as above 30kg/m², for example above 35 kg/m², such as above 40 kg/m².

In one embodiment the subject has a BMI above 30 kg/m².

In one embodiment the subject has a BMI above 35 kg/m².

Most people with diabetes develop high blood pressure during their life.Hypertension substantially increases the risk of diabetic complications.Diabetic complications include but are not limited to macrovascular andmicrovascular complications, including stroke, coronary artery disease,and peripheral vascular disease, retinopathy, nephropathy, and possiblyneuropathy. Hypertension may also lead to worsening of diabeticcomplications. Thus, control or alleviation of hypertension is often animportant aspect in the treatment of diabetic subjects.

In one embodiment, the tesofensine-metoprolol treatment described hereinleads to an alleviation or improvement of diabetic complications.

In one embodiment, the subject is suffering from diabetes, such as type1 diabetes, type 2 diabetes, pre-diabetes and gestational diabetes.

In one embodiment, the subject is suffering from type 1 diabetes.

In one embodiment, the subject is suffering from type 2 diabetes.

In one embodiment, the subject is suffering from pre-diabetes.

In one embodiment, the subject is suffering from gestational diabetes.

Type 1 diabetes (diabetes mellitus type 1) is a form of diabetes thatresults from the autoimmune destruction of the insulin-producing betacells in the pancreas. In type 1 diabetes, hypertension may reflect theonset of diabetic nephropathy.

Type 2 diabetes is a metabolic disorder that is characterized byhyperglycemia in the context of insulin resistance and a relative lackof insulin. Type 2 diabetes makes up about 90% of cases of diabetes,with the other 10% due primarily to diabetes mellitus type 1 andgestational diabetes. Obesity is thought to be the primary cause of type2 diabetes in people who are genetically predisposed to the disease. Intype 2 diabetes, hypertension is often present as part of the metabolicsyndrome of insulin resistance also including central obesity anddyslipidemia.

Pre-diabetes is used interchangeably herein with intermediatehyperglycaemia. Intermediate hyperglycaemia is a biochemical state inwhich a person has glucose levels above the normal range, but does notyet meet the criteria for a diagnosis of diabetes. The primary aim ofmanagement of intermediate hyperglycaemia is to prevent progression todiabetes.

A pre-diabetic subject may have one or more of impaired fastingglycaemia (IFG) and/or impaired glucose tolerance (IGT) and/or elevatedglycated haemoglobin (HbA_(1c)) levels.

Weight loss can prevent progression of pre-diabetes into diabetes andcan also markedly improve clinical symptoms of type 2 diabetes. Thus,weight loss is an attractive treatment strategy for pre-diabeticsubjects and subjects suffering from type 2 diabetes.

In one embodiment the subject is an obese, pre-diabetic human. In oneembodiment the subject is an obese subject suffering from type 2diabetes.

Gestational diabetes is a condition in which women without previouslydiagnosed diabetes exhibit high blood glucose levels during pregnancy(especially during their third trimester). Gestational diabetes iscaused when insulin receptors do not function properly.

The WHO diabetes diagnostic criteria are shown in the table below.

2 hour glucose* Fasting glucose HbA_(1c) mmol/l mmol/l mmol/molCondition (mg/dl) (mg/dl) (DCCT %) Normal <7.8 (<140) <6.1 (<110) <42(<6.0) Impaired <7.8 (<140) ≥6.1 (≥110) & 42-46 (6.0-6.4) fasting <7.0(<126) glycaemia Impaired ≥7.8 (≥140) <7.0 (<126) 42-46 (6.0-6.4)glucose tolerance Diabetes ≥11.1 (≥200) ≥7.0 (≥126) ≥48 (≥6.5) mellitus*Venous plasma glucose 2 hours after ingestion of 75 g oral glucose load

The subject benefitting from co-treatment of tesofensine and metoprololaccording to the methods of the present invention may also be a subjectsuffering from an obesity-associated disorder or condition, such as oneselected from the group consisting of metabolic syndrome, dyslipidemia,atherosclerosis, drug-induced obesity, overeating disorders, bulimianervosa, binge eating disorder, compulsive over-eating, impairedappetite regulation, Prader-Willi Syndrome, nonalcoholic fatty liverdisease (NAFLD) and nonalcoholic steatohepatitis (NASH).

In one embodiment the subject is suffering from metabolic syndrome.

In one embodiment, the subject is suffering from Prader Willi syndrome.Prader-Willi syndrome (PWS) is a genetic disorder due to loss offunction of specific genes on chromosome 15. In newborns symptomsinclude weak muscles, poor feeding, and slow development. In childhoodthe person becomes constantly hungry which often leads to obesity andtype 2 diabetes.

In one embodiment the subject is suffering from a fatty liver diseaseselected from nonalcoholic fatty liver disease (NAFLD) and nonalcoholicsteatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD) is a cause of a fatty liver,occurring when fat is deposited in the liver (steatosis) due to othercauses than excessive alcohol use. NAFLD is the most common liverdisorder in Western industrialized nations. NAFLD is associated withinsulin resistance and metabolic syndrome (obesity, combinedhyperlipidemia, diabetes mellitus (type II) and high blood pressure).Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD,and is a major cause of cirrhosis of the liver. NASH is a state in whichthe steatosis is combined with inflammation and fibrosis(steatohepatitis).

In one embodiment, the obesity-associated disorder or condition isnonalcoholic fatty liver disease (NAFLD).

In one embodiment, the obesity-associated disorder or condition isnonalcoholic steatohepatitis (NASH).

In one embodiment, the present disclosure relates to a method forco-treatment of hypertension and obesity in a subject in need thereof,the method comprising administering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure and body weight of said subject.

Co-administration of tesofensine and metoprolol is capable of preventingcardiovascular side-effects of tesofensine, i.e. prevent increases inheart rate and blood pressure induced by tesofensine. Thus, in oneembodiment, the present disclosure further relates to prevention oralleviation of cardiovascular side-effects of tesofensine.

In one embodiment, the present disclosure relates to a method forreduction of weight and blood pressure in a subject in need thereof, themethod comprising administering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure and weight of said subject.

In one embodiment, the present disclosure relates to a method forco-treatment of hypertension and diabetes (in particular type 2diabetes) in a subject in need thereof, the method comprisingadministering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure and treating diabetes of said        subject.

In one embodiment, the present disclosure relates to a method forco-treatment of hypertension and an obesity related disorder as hereindefined in a subject in need thereof, the method comprisingadministering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure and treating the obesity related        disorder of said subject.

In one embodiment, the present disclosure relates to a method forco-treatment of hypertension and a fatty liver disease, such as NAFLD orNASH, in a subject in need thereof, the method comprising administeringto said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof,        thereby reducing blood pressure and treating the fatty liver        disease of said subject.

In one embodiment the present disclosure relates to a method fortreatment of hypertension, obesity and diabetes in a subject in needthereof, the method comprising administering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof.

In one embodiment the present disclosure relates to a method fortreating, alleviating or preventing diabetic complications in a subjectin need thereof, the method comprising administering to said subject:

-   -   i) a therapeutically effective amount of tesofensine or a        pharmaceutically acceptable salt thereof; and    -   ii) a therapeutically effective amount of metoprolol or a        pharmaceutically acceptable salt thereof.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension and obesity.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension and diabetes.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension and a fatty liver disorder.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension and an obesity related disorder as hereindefined.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use in thetreatment of hypertension, obesity and diabetes.

In one embodiment, the present disclosure relates to a compositioncomprising tesofensine or a pharmaceutically acceptable salt thereof andmetoprolol or a pharmaceutically acceptable salt thereof, for use intreating, alleviating or preventing diabetic complications.

In one embodiment, the present disclosure relates to the use of acomposition comprising tesofensine or a pharmaceutically acceptable saltthereof and metoprolol or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of hypertension,optionally further for the treatment of obesity and/or diabetes.

The tesofensine and metoprolol according to the present disclosure maybe administered simultaneously, sequentially or separately.

In one embodiment, the tesofensine and the metoprolol areco-administered as a single composition. In such compositions, at leastpart of the metoprolol may advantageously be formulated to exhibit anextended release profile. In one embodiment, the composition comprisingtesofensine and metoprolol is as described in WO 2016/138908 (claimingpriority from PA 2015 70117 and PA 2015 70644), which are incorporatedby reference in their entirety.

An example of a single composition comprising both tesofensine andmetoprolol is a pharmaceutical composition comprising

a. a first composition comprising an extended release (ER) compositionof metoprolol or a pharmaceutically acceptable salt thereof,b. a second composition comprising tesofensine or a pharmaceuticallyacceptable salt thereof, andc. a third composition comprising an immediate release (IR) compositionwith metoprolol or a pharmaceutically acceptable salt thereof.

In one embodiment Tesofensine and Metoprolol are present in one dosageform with three phases in the following absolute amounts per dosageform.

Metoprolol extended Metoprolol immediate Tesofensine immediate releaserelease release 20-200 mg 5-50 mg 0.1-1.5 mg 75-125 mg 10-25 mg0.25-0.75 mg 75-80 mg 10-15 mg 0.25-0.75 mg 100 mg 25 mg 0.5 mg 100 mg10 mg 0.5 mg 80 mg 20 mg 0.5 mg 20 mg 5 mg 0.2 mg

In one embodiment, the dosage form comprises a tri-layer dosage unithaving an extended release (ER) phase layer with metoprolol, and oneimmediate release phase layer with metoprolol and another immediaterelease layer with tesofensine. The ER phase contains a therapeuticallyeffective amount of metoprolol, suitably in granulate form.

In other embodiments, the dosage form is a bi-layer tablet having an ERphase layer with metoprolol and one immediate release layer with bothmetoprolol and tesofensine.

The composition comprising tesofensine and metoprolol may furthercomprise one or more adjuvants, excipients, carriers and/or diluents.

In some embodiments, the composition comprising tesofensine andmetoprolol may comprise one or more further therapeutic and/orprophylactic agents known in the art to treat hypertension and/orobesity and/or diabetes.

The tesofensine and metoprolol may be administered by any convenientroute, which suits the desired therapy. Preferred routes ofadministration include oral administration, in particular in tablet, incapsule, in drage, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. Preferably, the tesofensine and metoprolol areadministered orally.

Compositions comprising tesofensine and metoprolol as described hereinmay be manufactured by the skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The subject treated is preferably a human, such as an adult human aged18 or older. In other embodiments the subject is a child or anadolescent below 18 years of age.

The data in the present application shows that co-administration oftesofensine and metoprolol unexpectedly result in a significant decreasein both systolic and diastolic blood pressure. The effect on bloodpressure in response to co-administration of tesofensine and metoprololis greater than has been shown by metoprolol alone (Kostis et al(Circulation 75(1), 204-212, 1987).

Thus, in one embodiment, the present disclosure relates to a method forimproving the therapeutic effect of metoprolol, particularly forimproving the effect of metoprolol on blood pressure, the methodcomprising co-administration of metoprolol and tesofensine as describedherein to a subject in need thereof.

EXAMPLES Example 1. Effect of Tesofensine on Metoprolol Pharmacokinetics

The ability of tesofensine to inhibit CYP2D6 in the clinical setting wasinvestigated in a Phase 1 drug-drug interaction (DDI) study withmetoprolol, which is a known substrate for CYP2D6.

Subjects

Healthy human male volunteers, 18-50 years of age. A total of 14subjects were included in the study.

Methodology

Two consecutive study periods separated by a washout period of at leastthree days. The sequence of events was the same for all subjects. Inperiod 1, a single dose of metoprolol was administered. In period 2, thesame dose of metoprolol was administered at a steady state concentrationof tesofensine.

Metoprolol: 50 mg single doseTesofensine: 2 mg loading dose at days 1-3, 0.5 mg maintenance dose atdays 4-14

Results

The single dose metoprolol pharmacokinetics (PK) obtained at day 0 wascompared to the PK obtained after 14 days of tesofensine once dailyadministration.

The results are depicted in FIG. 1. The results show that tesofensinecaused a small (15%), but statistically significant increase inmetoprolol AUC with no effect on either Tmax or Cmax. The resultsindicate that tesofensine is capable of increasing the bioavailabilityof metoprolol through its inhibitory action on CYP2D6.

Example 2. Effect of Tesofensine and Metoprolol on Heart Rate and BloodPressure in Humans

In a retrospective analysis of the data obtained in the above-mentionedPhase 1 DDI study the effect of a single dose of metoprolol in subjectstreated with tesofensine was investigated. Particularly, the effect oftesofensine-metoprolol on heart rate and blood pressure at rest, wasinvestigated.

Metoprolol was found to normalize the tesofensine-induced increase inheart rate after 7 hours (FIG. 2, 3^(rd) column) as previously shownpre-clinically. In accordance with the pharmacokinetics of metoprolol(plasma T_(1/2) 3-4 hours)—the effect on the heart rate disappearedafter ˜24 hours (FIG. 2, 4^(th) column). The data indicates thatco-administration of tesofensine and metoprolol is capable of inhibitingthe tesofensine-induced increase in heart rate in human subjects tolevels approximating pre-treatment levels.

In the present study, 14 days of tesofensine treatment was found toincrease systolic BP slightly, while diastolic BP was essentially notaltered by tesofensine treatment (FIG. 3, column 2). The slight increasein systolic BP in response to tesofensine treatment was not significant.However, statistically significant decreases in the systolic anddiastolic blood pressures were observed after metoprolol administrationat day 14 (FIG. 3, column 3) as compared to pre-treatment levels andalso compared to subjects treated with tesofensine only. Systolic BP inresponse to tesofensine-metoprolol co-administration was found to bedecreased by about 11 mm Hg as compared to pre-treatment levels and byabout 14 mm Hg as compared to subjects treated with tesofensine only.Diastolic BP in response to tesofensine-metoprolol co-administration wasfound to be decreased by about 12 mm Hg as compared to pre-treatmentlevels and by about 13 mm Hg as compared to subjects treated withtesofensine only. This corresponds to a decrease in systolic BP by morethan 8% and a decrease in diastolic BP by more than 15% as compared topre-treatment levels.

The data presented herein indicates that co-administration oftesofensine and metoprolol significantly reduce both systolic anddiastolic BP to a larger degree than metoprolol treatment alone (Kostiset al (Circulation 75(1), 204-212, 1987). Thus, the data hereinindicates that tesofensine and metoprolol co-administration is anattractive treatment strategy for hypertensive subjects. In particularfor treatment of obese hypertensive subjects as such subjects wouldbenefit greatly from both the weight-reducing effect of tesofensine andthe BP-lowering effect of tesofensine and metoprolol.

As shown herein, tesofensine may increase bioavailability of metoprololslightly through its inhibitory effect on CYP2D6 (Example 1). However,it is unlikely that the significant decrease in blood pressure describedherein in human subjects in response to tesofensine-metoprololco-administration can be explained solely by this action. Additionally,the blood pressure lowering effect of tesofensine-metoprololco-administration was highly surprising in view of animal studiesshowing that co-administration of tesofensine and metoprolol merelyprevented tesofensine-induced increases in heart rate and blood pressure(WO 2013/120935 and Hjorth Bentzen et al 2013; Obesity; Vol 21(5), p.985-992).

Example 3 Phase 2a Trial Entitled “A Double-Blind, Randomized,Placebo-Controlled, Multiple-Dose, Two-Center Safety, and Efficacy Studyof Co-Administration of Tesofensin/Metoprolol (Tesomet) in Subjects withType 2 Diabetes Mellitus (NCT02737891)

The trial comprised a total of 60 patients with a mean BMI of 32.59randomized into two groups of each 30 patients: Arm 1 were administeredtesofensine 0.5 mg (tablets)+metoprolol 100 mg (MetoHEXAL® 100 mg retardtablets) once a day (Tesomet); Arm 2 were administered Placebo matchingtablets once a day. Patients were treated for 90 days. The patients atenrolment had an average BMI of 32.59.

Inclusion Criteria:

1. Males and females2. Confirmed diagnosis of T2DM3. 18-70 years of age

4. HbA1c≥7.0% Exclusion Criteria:

1. Hypersensitivity to tesofensine/metoprolol2. Heart failure class II or greater according to the New York HeartAssociation (NYHA) or decompensated heart failure3. History of myocardial infarction or stroke within 12 months prior toenrolment4. History of coronary revascularisation or angioplasty in the last 12months prior to enrolment5. Patients reporting angina in the last 6 months prior to enrolment6. Treatment with insulin and/or other injectable anti-diabeticmedications, or TZDs7. Any clinically significant cardiac arrhythmia

Results

58 patients completed the study. The study demonstrated a statisticallysignificant reduction in bodyweight during the course of the study (day0 to day 90) of 3.50 kg (3.54%) in the treatment group compared to areduction of 0.29 kg (0.31%) in the placebo group (p<0.0001). Thereduction in body weight correlated with a decrease in waistcircumference of 2.29 cm in the Tesomet treatment group compared to areduction of 0.03 cm for patients receiving placebo (p<0.007).

Both systolic and diastolic blood pressures were numerically reduced inthe treatment group from baseline at day 0 to day 90. Systolic bloodpressure was numerically reduced by an average of 3.10 mmHg for patientstreated with Tesomet compared to an average decrease of 0.66 mmHg forpatients dosed with placebo. Diastolic blood pressure was numericallyreduced by an average of 2.21 mmHg for patients treated with Tesometcompared to an average decrease of 0.19 mmHg for patients dosed withplacebo.

1. A method for treating hypertension or pre-hypertension in ahypertensive or pre-hypertensive subject, comprising administering tosaid subject: i) 0.1 mg to 1 mg of tesofensine or a pharmaceuticallyacceptable salt thereof; ii) 10 mg to 200 mg of metoprolol or apharmaceutically acceptable salt thereof.
 2. (canceled)
 3. The methodaccording to claim 1, wherein the subject is suffering frompre-hypertension, stage 1 hypertension, stage 2 hypertension or isolatedsystolic hypertension, prior to the administration.
 4. The methodaccording to claim 1, wherein the subject has a systolic blood pressurein the range of 120-139 mmHg and a diastolic blood pressure in the rangeof 80-89 mmHg, prior to the administration.
 5. The method according toclaim 1, wherein the subject has a systolic blood pressure above 135mmHg and/or a diastolic blood pressure above 85 mmHg, prior to theadministration.
 6. The method according to claim 1, wherein the subjecthas a systolic blood pressure above 140 mmHg and/or a diastolic bloodpressure above 90 mmHg, prior to the administration.
 7. The methodaccording to claim 1, wherein the subject has a systolic blood pressurein the range of 140-159 mmHg and a diastolic blood pressure in the rangeof 90-99 mmHg, prior to the administration.
 8. The method according toclaim 1, wherein the subject has a systolic blood pressure in the rangeof 160-179 mmHg and a diastolic blood pressure in the range of 100-109mmHg, prior to the administration.
 9. The method according to claim 1,wherein the subject has a systolic blood pressure at or above 140 mmHgand a diastolic blood pressure below 90 mmHg, prior to theadministration.
 10. The method according to claim 1, wherein the subjectis a child or an adolescent having an average systolic blood pressure(SBP) or diastolic blood pressure (DBP) that is ≥95th percentile forgender, age, and height on at least 3 separate occasions or wherein thesubject has an average SBP or DBP levels that are ≥90th percentile but<95th percentile, prior to the administration.
 11. The method accordingto claim 1, wherein the subject is obese, prior to the administration.12. The method according to claim 1, wherein the subject has a BMI above25 kg/m².
 13. The method according to claim 12, wherein the subject hasa BMI above 30 kg/m².
 14. The method according to claim 1, wherein thesubject is suffering from diabetes, prior to the administration.
 15. Themethod according to claim 14, wherein the diabetes is type 1 diabetes,type 2 diabetes, pre-diabetes, or gestational diabetes.
 16. The methodaccording to claim 14, wherein the subject is suffering from type 1diabetes, prior to the administration.
 17. The method according to claim14, wherein the subject is suffering from type 2 diabetes, prior to theadministration.
 18. The method according to claim 14, wherein thesubject is suffering from pre-diabetes, prior to the administration. 19.The method according to claim 14, wherein the subject is suffering fromgestational diabetes, prior to the administration.
 20. The methodaccording to claim 1, wherein the subject is further suffering from adisorder or condition that is metabolic syndrome, dyslipidemia,atherosclerosis, drug-induced obesity, an overeating disorder, bulimianervosa, binge eating disorder, compulsive over-eating, impairedappetite regulation, Prader Willi Syndrome (PWS), nonalcoholic fattyliver disease (NAFLD), or nonalcoholic steatohepatitis (NASH) prior tothe administration.
 21. The method according to claim 1, wherein thesubject is a human.
 22. The method according to claim 1, wherein theadministration results in a decrease in the systolic blood pressure ofthe subject and/or a decrease in the diastolic blood pressure of thesubject, as compared to prior to the administration.
 23. The methodaccording to claim 1, wherein the administration results in a decreasein the systolic blood pressure by at least 5 mm Hg, as compared to thesubject's systolic blood pressure prior to the administration.
 24. Themethod according to claim 1, wherein the administration results in adecrease in the systolic blood pressure by at least 5%, as compared tothe subject's systolic blood pressure prior to the administration. 25.The method according to claim 1, wherein the administration results in adecrease in the diastolic blood pressure by at least 5 mm Hg, ascompared to the subject's diastolic blood pressure prior to theadministration.
 26. The method according to claim 1, wherein theadministration results in a decrease in the diastolic blood pressure byat least 5%, as compared to the subject's diastolic blood pressure priorto the administration.
 27. The method according to claim 1, wherein thetesofensine or a pharmaceutically acceptable salt thereof and themetoprolol or a pharmaceutically acceptable salt thereof areadministered orally.
 28. The method according to claim 1, wherein thetesofensine or a pharmaceutically acceptable salt thereof and themetoprolol or a pharmaceutically acceptable salt thereof areadministered simultaneously, sequentially or separately.
 29. The methodaccording claim 1, wherein the tesofensine or a pharmaceuticallyacceptable salt thereof and the metoprolol or a pharmaceuticallyacceptable salt thereof are co-administered as a single pharmaceuticalcomposition.
 30. The method according to claim 1, wherein the metoprololor a pharmaceutically acceptable salt thereof are administered as apharmaceutical composition having an extended release profile.
 31. Themethod according to claim 1, wherein the tesofensine or apharmaceutically acceptable salt thereof is administered to said subjectat a dose of 0.25 mg to 0.75 mg of tesofensine per day.
 32. The methodaccording to claim 1, wherein the metoprolol or a pharmaceuticallyacceptable salt thereof is administered to said subject at a dose of25-100 mg of metoprolol per day.
 33. (canceled)
 34. (canceled) 35.(canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)
 39. (canceled)40. (canceled)
 41. (canceled)
 42. (canceled)
 43. (canceled)
 44. Themethod according to claim 1, wherein the administration results inreduction of the subject's BMI, as compared to prior to theadministration.
 45. The method according to claim 14, wherein theadministration results in alleviation of the diabetes.
 46. The methodaccording to claim 14, wherein the administration results in alleviationof diabetic complications in the subject.
 47. The method according toclaim 20, wherein the subject is suffering from a fatty liver disorderand wherein the administration results in reduction of the fatty liverdisorder, as compared to prior to the administration.